http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, Early Online: 1–4 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2014.990155
RESEARCH ARTICLE
Reduced central corneal thickness in patients with isotretinoin treatment Nilay Yuksel1, Mediha Dilek Ozer2, Emine Akcay3, Umut Ozen3, and Selda Uzun4 Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Selcuk Universitesi on 02/04/15 For personal use only.
1
Department of Ophthalmology, Ataturk Training and Research Hospital, Ankara, Turkey, 2Department of Ophthalmology, Necip Fazil City Hospital, Kahramanmaras, Turkey, 3Department of Ophthalmology, Yildirim Beyazit University, Ankara, Turkey, and 4Department of Dermatology, Megapark Hospital, Kahramanmaras, Turkey Abstract
Keywords
Context: It is well known that oral isotretinoin treatment causes numerous ocular side-effects. Objective: To investigate the effect of systemic isotretinoin treatment on central corneal thickness (CCT) values due to meibomian gland disease (MGD). Participants: In this prospective study, 47 patients (27 men, 20 women) with nodulocystic acne vulgaris treated with oral isotretinoin (0.8 mg/kg daily) were included. Methods: All patients were analyzed with the Pentacam Scheimpflug topography at baseline, on the 3rd and 6th month of treatment. Main outcome measures were MGD scores and CCT. Results: The mean age of patients was 25.1 ± 4.4 years. The mean MGD scores were significantly higher at 3rd month (1.3 ± 0.9) and 6th month (1.5 ± 1.0) of treatment compared with baseline (1.1 ± 0.9) (p50.001). The mean CCT value at baseline was 540.5 ± 22.1 mm; 536.9 ± 20.5 mm at 3rd month and 531.4 ± 22.2 mm at 6th month. The differences between baseline and 6th month CCT measurements were statistically significant (p50.001). There was negative correlation between mean MGD scores and CCT values at the 6th month of treatment which was statistically significant (p ¼ 0.038, r ¼ 0.221). Conclusion: Isotretinoin treatment causes higher MGD scores. A statistically significant decrease in CCT due to MGD was detected at 6th month of treatment.
Acne vulgaris, central corneal thickness, isotretinoin, meibomian gland dysfunction
Introduction Acne vulgaris is one of the most common disorders for which patients seek dermatologic care1. Isotretinoin (13-cis retinoic acid) has been approved by the Food and Drug Administration (FDA) for the treatment of cystic and nodular acne, which is not responsive to other forms of treatment2,3. Besides significant systemic side-effects, numerous ocular side-effects associated with systemic use of isotretinoin have been reported as well4–10. Isotretinoin works for the treatment of acne in part by inhibiting sebaceous gland function. The association of isotretinoin and mebomian gland disease (MGD) have also been reported11–13. The evaluation of central corneal thickness (CCT) provides information about corneal health. CCT has a clinical and practical importance in refractive surgery, contact lens wear and ocular disorders such as glaucoma, and keratoconus14–17. Akyol-Salman et al. evaluated CCT values in patients with MGD and in normal subjects18. They did not find significant differences between the two groups. The effects of systemic isotretinoin treatment on anterior chamber parameters have been studied and have found Address for correspondence: Dr Nilay Yuksel, MD. E-mail: ozturk.nilay @gmail.com
History Received 8 October 2014 Revised 25 October 2014 Accepted 5 November 2014 Published online 19 January 2015
decreased CCT during isotretinoin treatment19. In this study, we aimed to evaluate possible CCT changes associated with MGD due to systemic isotretinoin treatment using the Pentacam (Oculus, Inc., Wetzlar, Germany).
Methods Forty seven patients (27 men, 20 women; mean age: 25.1 ± 4.4 years; age range: 17–37) with nodulocystic acne vulgaris treated with oral isotretinoin (0.8 mg/kg daily) were included in this prospective study. The study was performed from March 2013 to July 2014 at Kahramanmaras Necip Fazil City Hospital. Patients with any other systemic or ocular treatment, contact lens wear, dry eye, keratitis, allergic ocular disease, ocular surface disease, glaucoma, active and chronic uveitis, previous ocular surgery or injury were excluded from this study. Only right eye of each subject was evaluated. Written informed consent was obtained from each patient, and the study was approved by the institutional review board at Yildirim Beyazit University in accordance with the tenets of the Declaration of Helsinki. Patients underwent a full ophthalmological examination including refraction, external eye examination, slit-lamp and fundus examination at baseline, at 3rd and 6th month of treatment. A slit lamp examination was used to examine the meibomian glands. The meiobomian gland
2
N. Yuksel et al.
Cutan Ocul Toxicol, Early Online: 1–4
dysfunction was graded as 0, no obstruction; grade 1, plugging with translucent serous secretion when the lid margin is compressed; grade 2, plugging with viscous or waxy white secretion when the lid margin is compressed and grade 3, plugging with no secretion when the lid margin is compressed20.
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Selcuk Universitesi on 02/04/15 For personal use only.
Corneal thickness measurements The Pentacam is a rotating Scheimpflug camera that provides 50 cross-sectional images wihin a few seconds and acquires three-dimensional images of the anterior segment21. A CCT measurement by Pentacam was carried out by a single welltrained physician. The patient was asked to look at a fixation target and the measurement automatically started whenever correct alignment with the corneal apex and focus was achieved. Patient eye movement was constantly monitored by the system, and the quality factor was automatically evaluated. Only scans with a quality factor of more than 95% were included. Means of three consecutive Pentacam measurements were obtained at the pupil center thickness, recorded as CCT. To avoid the diurnal variation in corneal thickness values, all tests were performed within the same time interval (from 10 AM to 14 PM) and at a temperature that ranged from 20 to 25 C and relative humidity that ranged from 35% to 45%22,23. Statistical analysis Statistical analysis was performed with SPSS software, version 16.0 (Statistical Package for the Social Sciences, SPSS Inc., Chicago, IL). The Kolmogorov–Smirnov test was used to examine the distribution of the numerical data. The normally distributed data of the groups were compared by paired t test; measurement differences with abnormal distribution were compared using a Wilcoxon test. A p value50.05 was considered statistically significant. Correlations between MGD scores and CCT values at the 3rd and 6th month were analyzed by Spearman correlation test.
Results The results of MGD scores and CCT values are summarized in Table 1. The mean MGD scores were significantly higher at 3rd month (1.3 ± 0.9) and 6th month (1.5 ± 1.0) of the treatment compared with baseline (1.1 ± 0.9) (p50.001). The mean CCT value at baseline was 540.5 ± 22.1 mm (range: 477–581); 536.9 ± 20.5 mm (range: 474–578) at 3rd month and 531.4 ± 22.2 mm (476–570) at 6th month. CCT changes were not statistically significant after the 3rd month of treatment (p ¼ 0.07). On the other hand, the differences Table 1. Mean ± SD values of the meibomian gland dysfunction scores and central corneal thickness.
Baseline 3rd month 6th month
MGD score
CCT (mm)
r
1.1 ± 0.9 (0–3) 1.3 ± 0.9 (0–3)* 1.5 ± 1.0 (0–3)*
540.5 ± 22.1 (477–581) 536.9 ± 20.5 (474–578) 531.4 ± 22.2 (476–570)*
0.442 0.221y
*p50.001 versus baseline. yp50.05. r: correlation coefficient
between baseline and 6th month CCT measurements were statistically significant (p50.001). There was negative correlation between mean MGD scores and CCT values at the 6th month of treatment which was statistically significant (p ¼ 0.038, r ¼ 0.221). Also, there was negative correlation between mean MGD scores and CCT values at the 3rd month of treatment which was not statistically significant (p ¼ 0.07, r ¼ 0.442). Ocular surface irritation that required treatment was not detected in any patients during the treatment course.
Discussion Isotretinoin is a valuable therapeutic agent for the treatment of severe acne vulgaris. Beside its association with many important systemic adverse effects, Fraunfelder et al. evaluated a total of 1741 spontaneous case reports and reported adverse ocular side-effects, using the World Health Organisation (1972) criteria4–10. Isotretinoin causes a dramatic reduction in sebaceous gland activity and sebum production, which leads to a significant decrease in the Propionibacterium acnes population24,25. These changes in sebaceous gland secretions and sebum production cause skin and mucous membrane abnormalities26. Landthaler et al. observed the inhibitory effect of isotretinoin on human skin sebaceous glands27. Lambert and Smith have also shown in the animal models that isotretinoin therapy increases the risk of blepharitis due to MGD, and this is the first experimental study that shows systemic isotretinoin treatment-related shrinkage of meibomian glands13. Mathers et al. observed meibomian glands that were significantly less dense and atrophic during isotretinoin theraphy12. Karalezli et al. have found that blepharitis, meibomitis, hyperemia and vascularization of the lid margin were significantly more frequent during treatment (36%) than at the start of the study (8%)28. Neudorfer et al. reported a strong association between isotretinoin treatment and hordeolum, chalazion and blepharitis11. Similarly, we observed higher MGD scores after the 3rd and 6th month of treatment. Meibomian glands secrete lipids into the tear film, forming a superficial lipid layer that stabilizes it. In 2011, MGD was defined by the International Workshop on Meibomian Gland Dysfunction as a chronic diffuse abnormality of the meibomian glands29. It is characterized by terminal duct obstruction or changes in the glandular secretion and subsequently tear evaporates, tear osmolarity rises, aqueous tear volume decreases and the inflammatory cycle starts30–32. Chronic irritation of the ocular surface due to dryness is followed by immune activation, and finally it results in decreases in the tear film thickness that normally range from 3 to 40 mm33,34. In addition, apoptosis in ocular surface tissues, including the central and peripheral corneal epithelium was demonstrated in an experimental dry eye study in mice35. Sanchis-Gimeno et al. and Liu and Pflugfelder found a statistically significant reduction in corneal thickness values in dry eyes33,34. Also, Rismondo and Ubels found the drug in the tear film36. So, isotretinoin and its metabolites in the tear film may directly irritate the ocular surface and may cause changes in CCT11. Akyol-Salman et al. evaluated CCT values in patients with MGD and in normal subjects with ultrasonic pachymetry18.
DOI: 10.3109/15569527.2014.990155
They did not find significant differences between the two groups. Cumurcu et al. evaluated changes in anterior segment parameters in 29 patients who use isotretinoin independent from MGD with the Pentacam19. They found statistically significant decrease in CCT between the pretreatment and 3rd and 6th month. In this current study we aimed to emphasize the possible effect of isotretinoin due to MGD on CCT in 47 patients with acne vulgaris with the Pentacam. While MGD scores increased during the course of treatment; significantly decreased CCT values were detected at the 6th month of treatment when compared to baseline.
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Selcuk Universitesi on 02/04/15 For personal use only.
Conclusions This study showed a relationship between MGD caused by isotretinoin and CCT. The small number of patients, lack of data about endothelial cell density and dry eye tests are limitations of this study. Also, CCT changes after cessation of treatment might be evaluated. Although acne affects the majority of the adolescent population, it also remains prevalent in adults, affecting up to 40–50% of men and women in their 20 s and 10–20% in their 40s37,38. In this population, CCT assessment is very important for refractive surgery and non-refractive corneal surgery and keratoconus. Further studies with a larger number of patients with different CCT measurement methods are required.
Declaration of interest None of the authors has a financial or proprietary interest in any method or material mentioned. The authors report no declarations of interest.
References 1. Stern RS. Acne therapy. Medication use and sources of care in office-based practice. Arch Dermatol 1996;132:776–780. 2. Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC. Current use and future potential role of retinoids in dermatology. Drugs 1997;53:358–384. 3. Cunliff WJ, van der Kerkhof PCM, Caputo R, et al. Roaccutane treatment guidelines: results of an international survey. Pharm Treatment 1997;194:351–357. 4. Kim RH, Armstrong AW. Current state of acne treatment: highlighting lasers, photodynamic therapy, and chemical peels. Dermatol Online J 2011;17:2. 5. DiGiovanna JJ. Systemic retinoid therapy. Dermatol Clin 2001;19: 161–167. 6. Leyden JJ, James WD. Staphylococcus aureus infection as a complication of isotretinoin therapy. Arch Dermatol 1987;123: 606–608. 7. Zane LT, Leyden WA, Marqueling AL, Manos MM. A populationbased analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. Arch Dermatol 2006;142: 1016–1022. 8. Bernstein CN, Nugent Z, Longobardi T, Blanchard JF. Isotretinoin is not associated with inflammatory bowel disease: a populationbased case-control study. Am J Gastroenterol 2009;104: 2774–2778. 9. Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001;45:515–519. 10. Fraunfelder FT, Fraunfelder FW, Edwards R. Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol 2001;132:299–305.
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11. Neudorfer M, Goldshtein I, Shamai-Lubovitz O, et al. Ocular adverse effects of systemic treatment with isotretinoin. Arch Dermatol 2012;148:803–808. 12. Mathers WD, Shields WJ, Sachdev MS, et al. Meibomian gland morphology and tear osmolarity: changes with accutane therapy. Cornea 1991;10:286–290. 13. Lambert RW, Smith RE. Pathogenesis of blepharoconjunctivitis complicating 13-cis-retinoic acid (isotretinoin) therapy in a laboratory model. Invest Ophthalmol Vis Sci 1988;29:1559–1564. 14. Doughty MJ, Zaman ML. Human corneal thickness and its impact on intraocular pressure measures: a review and meta-analysis approach. Surv Ophthalmol 2000;44:367–408. 15. Solomon OD. Corneal stress test for extended wear. CLAO J 1996; 22:75–78. 16. Auffarth GU, Wang L, Vo¨lcker HE. Keratoconus evaluation using the Orbscan Topography System. J Cataract Refract Surg 2000;26: 222–228. 17. de Sanctis U, Missolungi A, Mutani B, et al. Reproducibility and repeatability of central corneal thickness measurement in keratoconus using the rotating Scheimpflug camera and ultrasound pachymetry. Am J Ophthalmol 2007;144: 712–718. 18. Akyol-Salman I, Azisi S, Mumcu U, et al. Central corneal thickness in patients with meibomian gland dysfunction. Clin Exp Optom 2011;94:464–467. 19. Cumurcu T, Sener S, Ozsoy E, Doganay S. Changes in anterior chamber parameters with the Pentacam rotating scheimpflug and axial length measurements by ultrasound in patients who use isotretinoin. Curr Eye Res 2012;37: 395–398. 20. Lin PY, Tsai SY, Cheng CY, et al. Prevalence of dry eye among an elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology 2003;110:1096–1101. 21. Swartz T, Marten L, Wang M. Measuring the cornea: the latest developments in corneal topography. Curr Opin Ophthalmol 2007; 18:325–333. 22. Harper CL, Boulton ME, Bennett D, et al. Diurnal variations in human corneal thickness. Br J Ophthalmol 1996;80: 1068–1072. 23. Feng Y, Varikooty J, Simpson TL. Diurnal variation of corneal and corneal epithelial thickness measured using optical coherence tomography. Cornea 2001;20:480–483. 24. Stewart ME, Benoit AM, Stranieri AM, et al. Effect of oral 13-cisretinoic acid at three dose levels on sustainable rates of sebum secretion and on acne. J Am Acad Dermatol 1983;8: 532–538. 25. King K, Jones DH, Daltrey DC, Cunliffe WJ. A double-blind study of the effects of 13-cis-retinoic acid on acne, sebum excretion rate and microbial population. Br J Dermatol 1982;107: 583–590. 26. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid. Evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 1980;3:602–611. 27. Landthaler M, Kummermehr J, Wagner A, Plewig G. 13-cisRetinoic acid inhibits sebaceous glands in animals and humans: planimetry and in-vitro autoradiography. J Invest Dermatol 1980; 74:453. 28. Karalezli A, Borazan M, Altinors DD, et al. Conjunctival impression cytology, ocular surface, and tear-film changes in patients treated with systemic isotretinoin. Cornea 2009;28: 46–50. 29. Knop E, Knop N, Millar T, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci 2011;52: 1938–1978. 30. Shimazaki J, Sakata M, Tsubota K. Ocular surface changes and discomfort in patients with meibomian gland dysfunction. Arch Ophthalmol 1995;113:1266–1270. 31. Jackson WB. Blepharitis: current strategies for diagnosis and management. Can J Ophthalmol 2008;43:170–179. 32. Bron AJ, Tiffany JM. The contribution of meibomian disease to dry eye. Ocul Surf 2004;2:149–165.
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33. Sanchis-Gimeno JA, Lleo´-Pe´rez A, Alonso L, et al. Reduced corneal thickness values in postmenopausal women with dry eye. Cornea 2005;24:39–44. 34. Liu Z, Pflugfelder SC. Corneal thickness is reduced in dry eye. Cornea 1999;18:403–407. 35. Yeh S, Song XJ, Farley W, et al. Apoptosis of ocular surface cells in experimentally induced dry eye. Invest Ophthalmol Vis Sci 2003;44:124–129.
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36. Rismondo V, Ubels JL. Isotretinoin in lacrimal gland fluid and tears. Arch Ophthalmol 1987;105:416–420. 37. White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol 1998;39:34–37. 38. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol 2008;58: 56–59.
RESEARCH ARTICLE
Reduced central corneal thickness in patients with isotretinoin treatment Nilay Yuksel1, Mediha Dilek Ozer2, Emine Akcay3, Umut Ozen3, and Selda Uzun4 Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Selcuk Universitesi on 02/04/15 For personal use only.
1
Department of Ophthalmology, Ataturk Training and Research Hospital, Ankara, Turkey, 2Department of Ophthalmology, Necip Fazil City Hospital, Kahramanmaras, Turkey, 3Department of Ophthalmology, Yildirim Beyazit University, Ankara, Turkey, and 4Department of Dermatology, Megapark Hospital, Kahramanmaras, Turkey Abstract
Keywords
Context: It is well known that oral isotretinoin treatment causes numerous ocular side-effects. Objective: To investigate the effect of systemic isotretinoin treatment on central corneal thickness (CCT) values due to meibomian gland disease (MGD). Participants: In this prospective study, 47 patients (27 men, 20 women) with nodulocystic acne vulgaris treated with oral isotretinoin (0.8 mg/kg daily) were included. Methods: All patients were analyzed with the Pentacam Scheimpflug topography at baseline, on the 3rd and 6th month of treatment. Main outcome measures were MGD scores and CCT. Results: The mean age of patients was 25.1 ± 4.4 years. The mean MGD scores were significantly higher at 3rd month (1.3 ± 0.9) and 6th month (1.5 ± 1.0) of treatment compared with baseline (1.1 ± 0.9) (p50.001). The mean CCT value at baseline was 540.5 ± 22.1 mm; 536.9 ± 20.5 mm at 3rd month and 531.4 ± 22.2 mm at 6th month. The differences between baseline and 6th month CCT measurements were statistically significant (p50.001). There was negative correlation between mean MGD scores and CCT values at the 6th month of treatment which was statistically significant (p ¼ 0.038, r ¼ 0.221). Conclusion: Isotretinoin treatment causes higher MGD scores. A statistically significant decrease in CCT due to MGD was detected at 6th month of treatment.
Acne vulgaris, central corneal thickness, isotretinoin, meibomian gland dysfunction
Introduction Acne vulgaris is one of the most common disorders for which patients seek dermatologic care1. Isotretinoin (13-cis retinoic acid) has been approved by the Food and Drug Administration (FDA) for the treatment of cystic and nodular acne, which is not responsive to other forms of treatment2,3. Besides significant systemic side-effects, numerous ocular side-effects associated with systemic use of isotretinoin have been reported as well4–10. Isotretinoin works for the treatment of acne in part by inhibiting sebaceous gland function. The association of isotretinoin and mebomian gland disease (MGD) have also been reported11–13. The evaluation of central corneal thickness (CCT) provides information about corneal health. CCT has a clinical and practical importance in refractive surgery, contact lens wear and ocular disorders such as glaucoma, and keratoconus14–17. Akyol-Salman et al. evaluated CCT values in patients with MGD and in normal subjects18. They did not find significant differences between the two groups. The effects of systemic isotretinoin treatment on anterior chamber parameters have been studied and have found Address for correspondence: Dr Nilay Yuksel, MD. E-mail: ozturk.nilay @gmail.com
History Received 8 October 2014 Revised 25 October 2014 Accepted 5 November 2014 Published online 19 January 2015
decreased CCT during isotretinoin treatment19. In this study, we aimed to evaluate possible CCT changes associated with MGD due to systemic isotretinoin treatment using the Pentacam (Oculus, Inc., Wetzlar, Germany).
Methods Forty seven patients (27 men, 20 women; mean age: 25.1 ± 4.4 years; age range: 17–37) with nodulocystic acne vulgaris treated with oral isotretinoin (0.8 mg/kg daily) were included in this prospective study. The study was performed from March 2013 to July 2014 at Kahramanmaras Necip Fazil City Hospital. Patients with any other systemic or ocular treatment, contact lens wear, dry eye, keratitis, allergic ocular disease, ocular surface disease, glaucoma, active and chronic uveitis, previous ocular surgery or injury were excluded from this study. Only right eye of each subject was evaluated. Written informed consent was obtained from each patient, and the study was approved by the institutional review board at Yildirim Beyazit University in accordance with the tenets of the Declaration of Helsinki. Patients underwent a full ophthalmological examination including refraction, external eye examination, slit-lamp and fundus examination at baseline, at 3rd and 6th month of treatment. A slit lamp examination was used to examine the meibomian glands. The meiobomian gland
2
N. Yuksel et al.
Cutan Ocul Toxicol, Early Online: 1–4
dysfunction was graded as 0, no obstruction; grade 1, plugging with translucent serous secretion when the lid margin is compressed; grade 2, plugging with viscous or waxy white secretion when the lid margin is compressed and grade 3, plugging with no secretion when the lid margin is compressed20.
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Selcuk Universitesi on 02/04/15 For personal use only.
Corneal thickness measurements The Pentacam is a rotating Scheimpflug camera that provides 50 cross-sectional images wihin a few seconds and acquires three-dimensional images of the anterior segment21. A CCT measurement by Pentacam was carried out by a single welltrained physician. The patient was asked to look at a fixation target and the measurement automatically started whenever correct alignment with the corneal apex and focus was achieved. Patient eye movement was constantly monitored by the system, and the quality factor was automatically evaluated. Only scans with a quality factor of more than 95% were included. Means of three consecutive Pentacam measurements were obtained at the pupil center thickness, recorded as CCT. To avoid the diurnal variation in corneal thickness values, all tests were performed within the same time interval (from 10 AM to 14 PM) and at a temperature that ranged from 20 to 25 C and relative humidity that ranged from 35% to 45%22,23. Statistical analysis Statistical analysis was performed with SPSS software, version 16.0 (Statistical Package for the Social Sciences, SPSS Inc., Chicago, IL). The Kolmogorov–Smirnov test was used to examine the distribution of the numerical data. The normally distributed data of the groups were compared by paired t test; measurement differences with abnormal distribution were compared using a Wilcoxon test. A p value50.05 was considered statistically significant. Correlations between MGD scores and CCT values at the 3rd and 6th month were analyzed by Spearman correlation test.
Results The results of MGD scores and CCT values are summarized in Table 1. The mean MGD scores were significantly higher at 3rd month (1.3 ± 0.9) and 6th month (1.5 ± 1.0) of the treatment compared with baseline (1.1 ± 0.9) (p50.001). The mean CCT value at baseline was 540.5 ± 22.1 mm (range: 477–581); 536.9 ± 20.5 mm (range: 474–578) at 3rd month and 531.4 ± 22.2 mm (476–570) at 6th month. CCT changes were not statistically significant after the 3rd month of treatment (p ¼ 0.07). On the other hand, the differences Table 1. Mean ± SD values of the meibomian gland dysfunction scores and central corneal thickness.
Baseline 3rd month 6th month
MGD score
CCT (mm)
r
1.1 ± 0.9 (0–3) 1.3 ± 0.9 (0–3)* 1.5 ± 1.0 (0–3)*
540.5 ± 22.1 (477–581) 536.9 ± 20.5 (474–578) 531.4 ± 22.2 (476–570)*
0.442 0.221y
*p50.001 versus baseline. yp50.05. r: correlation coefficient
between baseline and 6th month CCT measurements were statistically significant (p50.001). There was negative correlation between mean MGD scores and CCT values at the 6th month of treatment which was statistically significant (p ¼ 0.038, r ¼ 0.221). Also, there was negative correlation between mean MGD scores and CCT values at the 3rd month of treatment which was not statistically significant (p ¼ 0.07, r ¼ 0.442). Ocular surface irritation that required treatment was not detected in any patients during the treatment course.
Discussion Isotretinoin is a valuable therapeutic agent for the treatment of severe acne vulgaris. Beside its association with many important systemic adverse effects, Fraunfelder et al. evaluated a total of 1741 spontaneous case reports and reported adverse ocular side-effects, using the World Health Organisation (1972) criteria4–10. Isotretinoin causes a dramatic reduction in sebaceous gland activity and sebum production, which leads to a significant decrease in the Propionibacterium acnes population24,25. These changes in sebaceous gland secretions and sebum production cause skin and mucous membrane abnormalities26. Landthaler et al. observed the inhibitory effect of isotretinoin on human skin sebaceous glands27. Lambert and Smith have also shown in the animal models that isotretinoin therapy increases the risk of blepharitis due to MGD, and this is the first experimental study that shows systemic isotretinoin treatment-related shrinkage of meibomian glands13. Mathers et al. observed meibomian glands that were significantly less dense and atrophic during isotretinoin theraphy12. Karalezli et al. have found that blepharitis, meibomitis, hyperemia and vascularization of the lid margin were significantly more frequent during treatment (36%) than at the start of the study (8%)28. Neudorfer et al. reported a strong association between isotretinoin treatment and hordeolum, chalazion and blepharitis11. Similarly, we observed higher MGD scores after the 3rd and 6th month of treatment. Meibomian glands secrete lipids into the tear film, forming a superficial lipid layer that stabilizes it. In 2011, MGD was defined by the International Workshop on Meibomian Gland Dysfunction as a chronic diffuse abnormality of the meibomian glands29. It is characterized by terminal duct obstruction or changes in the glandular secretion and subsequently tear evaporates, tear osmolarity rises, aqueous tear volume decreases and the inflammatory cycle starts30–32. Chronic irritation of the ocular surface due to dryness is followed by immune activation, and finally it results in decreases in the tear film thickness that normally range from 3 to 40 mm33,34. In addition, apoptosis in ocular surface tissues, including the central and peripheral corneal epithelium was demonstrated in an experimental dry eye study in mice35. Sanchis-Gimeno et al. and Liu and Pflugfelder found a statistically significant reduction in corneal thickness values in dry eyes33,34. Also, Rismondo and Ubels found the drug in the tear film36. So, isotretinoin and its metabolites in the tear film may directly irritate the ocular surface and may cause changes in CCT11. Akyol-Salman et al. evaluated CCT values in patients with MGD and in normal subjects with ultrasonic pachymetry18.
DOI: 10.3109/15569527.2014.990155
They did not find significant differences between the two groups. Cumurcu et al. evaluated changes in anterior segment parameters in 29 patients who use isotretinoin independent from MGD with the Pentacam19. They found statistically significant decrease in CCT between the pretreatment and 3rd and 6th month. In this current study we aimed to emphasize the possible effect of isotretinoin due to MGD on CCT in 47 patients with acne vulgaris with the Pentacam. While MGD scores increased during the course of treatment; significantly decreased CCT values were detected at the 6th month of treatment when compared to baseline.
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Selcuk Universitesi on 02/04/15 For personal use only.
Conclusions This study showed a relationship between MGD caused by isotretinoin and CCT. The small number of patients, lack of data about endothelial cell density and dry eye tests are limitations of this study. Also, CCT changes after cessation of treatment might be evaluated. Although acne affects the majority of the adolescent population, it also remains prevalent in adults, affecting up to 40–50% of men and women in their 20 s and 10–20% in their 40s37,38. In this population, CCT assessment is very important for refractive surgery and non-refractive corneal surgery and keratoconus. Further studies with a larger number of patients with different CCT measurement methods are required.
Declaration of interest None of the authors has a financial or proprietary interest in any method or material mentioned. The authors report no declarations of interest.
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